In the present report, we describe a novel mutation (c.1834delC) in MCT8
detected in all AHDS affected members of a large Brazilian family.3,4
Mutations in MCT8
were originally reported in young boys with severe mental retardation and very recently, Schwartz et al
described mutations in this gene in six families with AHDS. There are very few reports on AHDS, but all cases reported so far are characterised by very severe mental retardation associated with various neurological dysfunctions. The inability to walk independently occurs in about 50% of patients, and speech is very compromised in all of them (Schwartz et al12
and this report). It has been suggested that the most severe forms present a phenotype that resembles cerebral palsy,2
and therefore, it seems that all pathogenic mutations found in MCT8
cause a spectrum of clinical variability of AHDS.
The mutation described by us, c.1834delC, seems not to lead to mRNA decay, as indicated both by its location in the last exon and by the results obtained with the functional analysis.13
It probably results in a frameshift, with bypassing of the wild type translation stop codon and the creation of a novel stop codon 196 nucleotides further downstream. This mRNA, translated in a protein with an abnormal C‐terminal domain with 64 additional amino acids, impairs thyroid hormone transport, the only known function of MCT8.14
Although MCT8 is capable of transporting both T3 and T4, only serum T3 and FT3, but not T4 and FT4, are increased in the AHDS patients, which has also been observed in other patients with mutations in this gene.7,8
This suggests that MCT8 is more important for T3 than for T4 metabolism.
Impaired T3 transport in AHDS patients was confirmed in this study through in vitro functional analysis of the mutated MCT8. Our findings demonstrate that the C‐terminal elongation of the MCT8 protein results in a drastic reduction of T3 transport. In addition, the strongly decreased metabolism of T3 by D3 in cells expressing mutated MCT8 compared with the wild type protein indicates that the defect in the transporter results in a large reduction in intracellular T3 availability.
MCT8 is expressed in several tissues, including liver, kidney, heart, and brain. The protein is localised in different brain areas, in particular the choroid plexus structures, neocortical and allocortical regions, striatum, and cerebellum.15
In the brain, MCT8 is localised primarily in neurones, which are the primary targets for the crucial action of T3 during fetal and neonatal brain development. This T3 is largely derived from the outer ring deiodination of T4 by the type II deiodinase (D2) in neighbouring astrocytes. MCT8 is thought to be essential for the uptake of this T3 by neurones. In addition to the nuclear receptors, which mediate the action of T3, neurones also express D3 for termination of T3 action. The defect in neuronal T3 uptake due to mutations in MCT8
will block T3 access to its intracellular receptor and degrading enzyme, with a resultant impairment of neurological development and decrease in T3 clearance.
We have observed that thyroid parameters observed in the patients with the mutation c.1834delC are less altered than in those whose disease is predicted to be due to lack of the transporter.7,8
Alternatively, considering the age of our patients (>20 years), it is possible that the abnormal thyroid parameters are more pronounced in younger patients. In this regard, it is of note that the oldest patient (II‐4) here reported, aged 62 years, had serum T3 levels close to the upper normal limit. Although the number of mutations in MCT8
is very small, different types of mutations have been described, including missense, inframe deletion, and creation of premature stop codons.7,8,12,16
It will be important to analyse the functional effects of these mutations in order to verify if there is any genotype– phenotype correlation.
All obligate carriers of the Brazilian family have normal cognitive functions. To date, there is apparently only one previous report describing a carrier female with mental retardation7
and slightly low T4 and FT4. This clinical variability possibly reflects an X inactivation deviation.
It will be interesting to investigate if in addition to an impaired CNS development, the neuromuscular abnormalities in patients with MCT8
mutations may be due to increased T3 uptake in affected muscles in the face of elevated circulating T3 levels. It is noteworthy that an excess of T3 causes muscle wasting.17,18
In conclusion, this work contributes to a better clinical and molecular characterisation of the Allan‐Herndon‐Dudley syndrome. In addition, based on our functional assays, we suggest that the neurological defect in these patients and the increased serum T3 levels are due to impaired uptake and metabolism of T3 in tissues, in particular brain. In addition, high serum T3 concentration may contribute to the dysfunction of skeletal muscle in these patients.